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Mitoxantrone impairs proteasome activity and prompts early energetic and proteomic changes in HL-1 cardiomyocytes at clinically relevant concentrations

  • Organ Toxicity and Mechanisms
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Abstract

Mitoxantrone (MTX) is used to treat several types of cancers and to improve neurological disability in multiple sclerosis. Unfortunately, cardiotoxicity is a severe and common adverse effect in MTX-treated patients. Herein, we aimed to study early and late mechanisms of MTX-induced cardiotoxicity using murine HL-1 cardiomyocytes. Cells were exposed to MTX (0.1, 1 or 10 µM) during short (2, 4, 6, or 12 h) or longer incubation periods (24 or 48 h). At earlier time points, (6 and 12 h) cytotoxicity was already observed for 1 and 10 µM MTX. Proteomic analysis of total protein extracts found 14 proteins with higher expression and 26 with lower expression in the cells exposed for 12 h to MTX (pH gradients 4–7 and 6–11). Of note, the expression of the regulatory protein 14-3-3 protein epsilon was increased by a factor of two and three, after exposure to 1 and 10 µM MTX, respectively. At earlier time-points, 10 µM MTX increased intracellular ATP levels, while decreasing media lactate levels. At later stages (24 and 48 h), MTX-induced cytotoxicity was concentration and time-dependent, according to the MTT reduction and lactate dehydrogenase leakage assays, while caspase-9, -8 and -3 activities increased at 24 h. Regarding cellular redox status, total glutathione increased in 1 µM MTX (24 h), and that increase was dependent on gamma-glutamylcysteine synthetase activity. Meanwhile, for both 1 and 10 µM MTX, oxidized glutathione was significantly higher than control at 48 h. Moreover, MTX was able to significantly decrease proteasomal chymotrypsin-like activity in a concentration and time-independent manner. In summary, MTX significantly altered proteomic, energetic and oxidative stress homeostasis in cardiomyocytes at clinically relevant concentrations and our data clearly demonstrate that MTX causes early cardiotoxicity that needs further study.

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Abbreviations

Ac-DEVD-pNA:

Acetyl-Asp-Glu-Val-Asp p-nitroanilide;

AUF:

Arbitrary units of fluorescence;

FBS:

Fetal bovine serum;

GSH:

Reduced glutathione;

GSSG:

Oxidized glutathione;

HF:

Heart failure;

LDH:

Lactate dehydrogenase;

LVEF:

Left ventricular ejection fraction;

MTT:

3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide;

MS:

Multiple sclerosis;

NAC:

N-acetyl-cysteine;

OD:

Optic density

PBS:

Phosphate buffered saline with calcium and magnesium;

ROS:

Reactive oxygen species;

tGSH:

Total glutathione

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Acknowledgments

We want to acknowledge the late Professor William Claycomb, Professor of Biochemistry and Molecular Biology at LSUHSC, USA for the donation of the HL-1 cell line. VMC acknowledges Fundação da Ciência e Tecnologia (FCT) for her grant (SFRH/BPD/110001/2015) as this work was funded by national funds through FCT – Fundação para a Ciência e a Tecnologia, I.P., under the Norma Transitória – DL57/2016/CP1334/CT0006. MS data was provided by the Mass Spectrometry Unit (UniMS), ITQB/iBET, Oeiras, Portugal. This work was supported by FEDER funds through the Operational Programme for Competitiveness Factors – COMPETE and by national funds by FCT within the project “PTDC/DTP-FTO/1489/2014 – POCI-01-0145-FEDER-016537”. This work received financial support from PT national funds (FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) through UIDB/04378/2020 (UCIBIO-REQUIMTE Associate Laboratory).

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Authors and Affiliations

  1. UCIBIO/REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal

    Vera Marisa Costa, João Paulo Capela, José Luís Dores-Sousa, Maria Lourdes Bastos, Fernando Remião & Félix Carvalho

  2. FP-ENAS, Fernando Pessoa Energy, Environment and Health Research Unit, Universidade Fernando Pessoa, Porto, Portugal

    João Paulo Capela

  3. UCIBIO/REQUIMTE, Faculty of Sciences and Technology, Nova University Lisboa, Monte Caparica, Portugal

    Joana R. Sousa, Rute P. Eleutério, Patrícia R. S. Rodrigues & M. Gabriela Almeida

  4. Department of Chemical Engineering, Vrije Universiteit Brussel, Brussels, Belgium

    José Luís Dores-Sousa

  5. Faculty of Sciences and Technology, Neurosciences Center of Coimbra, University of Coimbra, Coimbra, Portugal

    Rui A. Carvalho

  6. CIAFEL, Faculty of Sports, University of Porto, Porto, Portugal

    José Alberto Duarte

  7. CiiEM, Egas Moniz University Institute, Monte Caparica, Portugal

    M. Gabriela Almeida

  8. Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Kurt J. Varner

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  1. Vera Marisa Costa
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  2. João Paulo Capela
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Costa, V.M., Capela, J.P., Sousa, J.R. et al. Mitoxantrone impairs proteasome activity and prompts early energetic and proteomic changes in HL-1 cardiomyocytes at clinically relevant concentrations. Arch Toxicol 94, 4067–4084 (2020). https://doi.org/10.1007/s00204-020-02874-4

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